Sickle cell disease is an orphan disease and patients with high-risk features, including those with a history of cerebral vasculopathy and/or pulmonary and/or pulmonary vascular complications portend to have a poor prognosis with a high tendency toward serious chronic morbidities and premature death. The only curative and organ stabilizing therapy is allogeneic stem cell transplantation (AlloSCT) from unaffected human leukocyte antigen (HLA) matched sibling donors. However, only approximately 15% of SCD patients have such donors. An alternate allogeneic donor source includes unaffected FHI donors. The use of this donor source is limited by increased risks of graft-versus-host disease (GVHD) and/or graft failure. However, these risks can be minimized by the use of T cell depletion (TCD) through positive selection of CD34+ hematopoietic stem cells followed by minimal T cell addback. FHI TCD AlloSCT utilizing CD34+ hematopoietic stem cell positive selection has been demonstrated to be successful in patients with high-risk hematological malignancies. Currently there is no FDA indication for this device/procedure for non-malignant diseases, such as SCD. The specific objectives include: 1) to determine safety and feasibility of host myeloimmunosuppressive conditioning (MIC) followed by FHI TCD AlloSCT in high-risk patients with SCD; 2) sustained donor whole blood and red blood cell chimerism; 3) quality and quantity of immune cell reconstitution and function; 4) changes in neurological and neurocognitive sequelae; 5) differences in pulmonary and pulmonary vascular function; and 6) changes in health-related quality of life (HRQL).